Positive allosteric AMPA receptor modulators (PAARM), processes for preparing them, and their use as pharmaceutical compositions

ABSTRACT

Compounds of formula (I)  
                 
 
     wherein R 1 , R 2 , R 3 , R 4 , R 5 , n, and m, are as defined herein, or an enantiomer or diastereomer thereof, or a pharmacologically acceptable salt thereof; processes for preparing these compounds, and their use in pharmaceutical compositions.

RELATED APPLICATIONS

[0001] Benefit under 35 U.S.C. §119(e) of prior U.S. provisionalapplication Serial No. 60/303,292, filed Jul. 6, 2001, is hereby claimedand is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to new positive allosteric AMPAreceptor modulators, processes for preparing them, and their use aspharmaceutical compositions.

[0003] Compounds which are structurally similar to the compoundsaccording to the invention are disclosed in WO 99/67242 which describescarbapenem derivatives with an antibacterial activity, whereinnaphtho[1,8-de]-2,3-dihydro-1,1-dioxide-1,2-thiazine is used as asynthesis component.

SUMMARY OF THE INVENTION

[0004] The compounds according to the invention are compounds of generalformula (I)

[0005] wherein:

[0006] R¹ denotes a group selected from among hydrogen, a C₁-C₆-alkylgroup optionally substituted by one or more halogen atoms, —SO₂H,—SO₂—C₁-C₆-alkyl, —SO—C₁-C₆-alkyl, —CO—C₁-C₆-alkyl, —O,phenyl-C₁-C₄-alkyl, —C₁-C₄-alkyl-NR⁶R⁷, and —C₁-C₄-alkyl-O—C₁-C₄-alkyl,and C₃—C₆-cycloalkyl,

[0007] R² and R³, which may be identical or different, denote a groupselected from among hydrogen, a C₁-C₆-alkyl group optionally substitutedby one or more halogen atoms, halogen, —NO₂, —SO₂H, —SO₂—C₁-C₆-alkyl,—SO—C₁-C₆-alkyl, —CO—C₁-C₆-alkyl, —OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl,—C₁-C₄-alkyl-NR⁶R⁷, and —C₁-C₄-alkyl-O—C₁-C₄-alkyl, andC₃-C₆-cycloalkyl, or

[0008] R¹ and R² together denote a C₄-C₆-alkylene bridge;

[0009] R⁶ and R⁷, which may be identical or different, denote hydrogen,C₁-C₄-alkyl, or —CO—C₁-C₄-alkyl;

[0010] R⁸ and R⁹, which may be identical or different, denote hydrogenor C₁-C₄-alkyl;

[0011] R⁴, each of which may be identical or different, denotes a groupselected from among a C₁-C₆-alkyl group optionally substituted by one ormore halogen atoms, phenyl-C₁-C₄-alkyl, halogen, —CN, —NO₂, —SO₂H,—SO₃H, —SO₂—C₁-C₆-alkyl, —SO—C₁-C₆-alkyl, —SO₂—NR⁶R⁷, —COOH,—CO—C₁-C₆-alkyl, —O—CO—C₁-C₄-alkyl, —CO—O—C₁-C₄-alkyl,—O—CO—O—C₁-C₄-alkyl, —CO—NR⁶R⁷, —OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl,—NR⁶R⁷, and an aryl group optionally mono or polysubstituted by halogenatoms, —NO₂, —SO₂H, or C₁-C₄-alkyl;

[0012] R⁵, each of which may be identical or different, denotes a groupselected from among a C₁-C₆-alkyl group optionally substituted by one ormore halogen atoms, phenyl-C₁-C₄-alkyl, halogen, —CN, —NO₂, —SO₂H,—SO₃H, —SO₂—C₁-C₆-alkyl, —SO—C₁-C₆-alkyl, —SO₂—NR⁶R⁷, —COOH,—CO—C₁-C₆-alkyl, —O—CO—C₁-C₄-alkyl, —CO—O—C₁-C₄-alkyl,—O—CO—O—C₁-C₄-alkyl, —CO—NR⁶R⁷, —OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl,—NRR⁷ and an aryl group optionally mono or polysubstituted by halogenatoms, —NO₂, —SO₂H, or C₁-C₄-alkyl; and

[0013] n and m, which may be identical or different, represent 0, 1, 2,or 3,

[0014] with the proviso thatnaphtho[1,8-de]-2,3-dihydro-1,1-dioxide-1,2-thiazine is excluded,

[0015] optionally in the form of their various enantiomers anddiastereomers, and the pharmacologically acceptable salts thereof.

[0016] Preferred compounds are the compounds of general formula (I),wherein:

[0017] R¹ denotes a group selected from among hydrogen, a C₁-C₆-alkylgroup optionally substituted by one or more halogen atoms, —SO₂H,—SO₂—C₁-C₆-alkyl, —SO—C₁-C₆-alkyl, —CO—C₁-C₆-alkyl, —O,—C₁-C₄-alkyl-NR⁷R⁸, and —C₁-C₄-alkyl-O—C₁-C₄-alkyl, or benzyl,

[0018] R² and R³, which may be identical or different, denote a groupselected from among hydrogen, a C₁-C₆-alkyl group optionally substitutedby one or more halogen atoms, halogen, —NO₂, —SO₂H, —SO₂—C₁-C₆-alkyl,—SO—C₁-C₆-alkyl, —CO—C₁-C₆-alkyl, —OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl,—C₁-C₄-alkyl-NR⁶R⁷, and —C₁-C₄-alkyl-O—C₁-C₄-alkyl, or

[0019] R¹ and R² together denote a C₄-C₆-alkylene bridge;

[0020] R⁶ and R⁷, which may be identical or different, denote hydrogen,C₁-C₄-alkyl, or —CO—C₁-C₂-alkyl; and

[0021] R⁴, each of which may be identical or different, denotes a groupselected from among a C₁-C₆-alkyl group optionally substituted by one ormore halogen atoms, halogen, —CN, —NO₂, —SO₂H, —SO₃H, —COOH,—CO—C₁-C₆-alkyl, —O—CO—C₁-C₄-alkyl, —CO—O—C₁-C₄-alkyl,—O—CO—O—C₁-C₄-alkyl, —CO—NR⁶R⁷, —OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl, and—NR⁶R⁷;

[0022] R⁵, each of which may be identical or different, denotes a groupselected from among a C₁-C₆-alkyl group optionally substituted by one ormore halogen atoms, halogen, —CN, —NO₂, —SO₂H, —SO₃H, —COOH,—CO—C₁-C₆-alkyl, —O—CO—C₁-C₄-alkyl, —CO—O—C₁-C₄-alkyl,—O—CO—O—C₁-C₄-alkyl, —CO—NR⁶R⁷, —OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl, and—NR⁶R⁷; and

[0023] n and m, which may be identical or different, represent 0, 1, or2,

[0024] optionally in the form of the various enantiomers anddiastereomers thereof, as well as the pharmacologically acceptable saltsthereof.

[0025] Particularly preferred are compounds of general formula (I),wherein:

[0026] R¹ denotes hydrogen, C₁-C₄-alkyl, or benzyl,

[0027] R² and R³, which may be identical or different, denote hydrogenor C₁-C₄-alkyl, or

[0028] R¹ and R² together denote a butylene bridge;

[0029] R⁴, each of which may be identical or different, denotes a groupselected from among a C₁-C₆-alkyl group optionally substituted by one ormore halogen atoms, halogen, —CN, —NO₂, —COOH, —CO—C₁-C₆-alkyl,—O—CO—C₁-C₄-alkyl, —CO—O—C₁-C₄-alkyl, —O—CO—O—C₁-C₄-alkyl, —CO—NR⁶R⁷,—OH, —O—C₁-C₆-alkyl, —S—C₁-C₁-alkyl, and —NR⁶R⁷;

[0030] R⁵, each of which may be identical or different, denotes a groupselected from among a C₁-C₆-alkyl group optionally substituted by one ormore halogen atoms, halogen, —CN, —NO₂, —COOH, —CO—C₁-C₆-alkyl,—O—CO—C₁-C₄-alkyl, —CO—O—C₁-C₄-alkyl, —O—CO—O—C₁-C₄-alkyl, —CO—NR⁶R⁷,—OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl, and —NR⁶R⁷; and

[0031] n and m, which may be identical or different, represent 0, 1, or2,

[0032] optionally in the form of the various enantiomers anddiastereomers thereof, as well as the pharmacologically acceptable saltsthereof.

[0033] Also particularly preferred are compounds of general formula (I),wherein:

[0034] R¹, R², and R³, which may be identical or different, denotehydrogen or C₁-C₄-alkyl;

[0035] R⁴, which may be identical or different, denotes a group selectedfrom among a C₁-C₆-alkyl group optionally substituted by one or morehalogen atoms, halogen, —NO₂, —O—CO—C₁-C₄-alkyl, —O—CO—O—C₁-C₄-alkyl,—O—C —C₆-alkyl, and —NR⁶R⁷;

[0036] R⁵, which may be identical or different, denotes a group selectedfrom among a C₁-C₆-alkyl group optionally substituted by one or morehalogen atoms, halogen, —NO₂, —O—CO—C₁-C₄-alkyl, —O—CO—O—C₁-C₄-alkyl,—O—Cl—C₆-alkyl, and —NR⁶R⁷; and

[0037] n and m, which may be identical or different, represent 0, 1, or2,

[0038] optionally in the form of the various enantiomers anddiastereomers thereof, as well as the pharmacologically acceptable saltsthereof.

[0039] Of particular importance according to the invention are thecompounds of general formula (I), wherein R¹ denotes methyl, ethyl,isopropyl, n-butyl, or benzyl, optionally in the form of the variousenantiomers and diastereomers thereof, as well as the pharmacologicallyacceptable salts thereof.

[0040] Particularly preferred are compounds of general formula (I)wherein R¹ denotes methyl, optionally in the form of thepharmacologically acceptable salts thereof.

[0041] Also particularly preferred are compounds of general formula (I),wherein:

[0042] R¹ denotes methyl;

[0043] R² and R³ denote hydrogen;

[0044] R⁴ and R⁵, which may be identical or different, denote halogen,preferably fluorine, chlorine, or bromine, most preferably fluorine orchlorine; and

[0045] n and m, which may be identical or different, represent 0, 1, or2, preferably 0 or 1,

[0046] optionally in the form of the pharmacologically acceptable saltsthereof.

[0047] The alkyl groups used, unless otherwise stated, are branched andunbranched alkyl groups having 1 to 6 carbon atoms, preferably 1 to 4carbon atoms. Examples include: methyl, ethyl, propyl, butyl, pentyl,and hexyl. The groups methyl, ethyl, propyl, or butyl may optionallyalso be referred to by the abbreviations Me, Et, Pr, or Bu. Unlessotherwise stated, the definitions propyl, butyl, pentyl, and hexyl alsoinclude all possible isomeric forms of the groups in question. Thus, forexample, propyl includes n-propyl and isopropyl, butyl includesisobutyl, sec-butyl, and tert-butyl, etc.

[0048] In the abovementioned alkyl groups, one or more hydrogen atomsmay optionally be substituted by the halogen atoms fluorine, chlorine,bromine, or iodine. The substituents fluorine and chlorine arepreferred. The substituent fluorine is particularly preferred. Ifdesired, all the hydrogen atoms of the alkyl group may be replaced.

[0049] The alkyl group mentioned in the group phenyl-C₁-C₁-alkyl may bein branched or unbranched form. Unless otherwise stated benzyl andphenylethyl are preferred phenyl-C₁-C₄-alkyl groups. Benzyl isparticularly preferred.

[0050] The alkyl groups mentioned in the groups —SO₂—C₁-C₆-alkyl,—SO—C₁-C₆-alkyl, —CO—C₁-C₆-alkyl, —CO—C₁-C₄-alkyl, —C₁-C₄-alkyl-NR⁶R⁷,—C₁-C₄-alkyl—O—C₁-C₄-alkyl, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl,—O—CO—C₁-C₄-alkyl, —CO—O—C₁-C₄-alkyl, or —O—CO—O—C₁-C₄-alkyl may be inbranched or unbranched form with 1 to 6 carbon atoms, preferably with 1to 4 carbon atoms, particularly preferably with 1 to 3 carbon atoms,most preferably with 1 to 2 carbon atoms.

[0051] The C₄-C₆-alkylene bridge may, unless otherwise stated, bebranched and unbranched alkylene groups having 4 to 6 carbon atoms, forexample, n-butylene, 1-methylpropylene, 2-methylpropylene,1,1-dimethylethylene, 1,2-dimethylethylene, etc. n-Butylene bridges areparticularly preferred.

[0052] The aryl group is an aromatic ring system having 6 to 10 carbonatoms, preferably phenyl.

[0053] In the abovementioned aryl groups, one or more hydrogen atoms mayoptionally be substituted by halogen atoms, —NO₂, —SO₂H, or—C₁-C₄-alkyl, preferably fluorine, chlorine, —NO₂, ethyl, or methyl,most preferably fluorine or methyl.

[0054] The term C₃-C₆-cycloalkyl denotes saturated cyclic hydrocarbongroups having 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

[0055] The term halogen, unless otherwise stated, refers to fluorine,chlorine, bromine, and iodine, preferably fluorine, chlorine, andbromine, most preferably fluorine and chlorine, most preferablyfluorine.

[0056] As already mentioned, the compounds of formula (I) or the variousenantiomers and diastereomers thereof may be converted into the saltsthereof, particularly, for pharmaceutical use, into the physiologicallyand pharmacologically acceptable salts thereof. These salts may on theone hand take the form of physiologically and pharmacologicallyacceptable acid addition salts of the compounds of formula (I) withinorganic or organic acids. On the other hand, the compound of formula(I) where R¹ is hydrogen may be converted by reaction with inorganicbases into physiologically and pharmacologically acceptable salts withalkali or alkaline earth metal cations as counter-ions. The acidaddition salts may be prepared, for example, using hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,acetic acid, fumaric acid, succinic acid, lactic acid, citric acid,tartaric acid, or maleic acid. It is also possible to use mixtures ofthe above acids. For preparing the alkali and alkaline earth metal saltsof the compound of formula (I) wherein R¹ denotes hydrogen, it ispreferable to use the alkali and alkaline earth metal hydroxides andhydrides, the hydroxides and hydrides of the alkali metals, especiallysodium and potassium, being preferred, while sodium and potassiumhydroxide are particularly preferred.

DETAILED DESCRIPTION OF THE INVENTION

[0057] The compounds according to the invention may be prepared in amanner known per se. The following general methods of synthesis 1 and 2shown in Diagrams 1 and 2 below are meant to illustrate the inventionwithout restricting it to their content.

[0058] Starting from a compound of formula (II), a compound of formula(III) is prepared by sulfonation and subsequent chlorination. Thecompound of formula (IV) obtained after condensation with aminoaceticacid derivatives is cyclized by adding polyphosphoric acid to the targetcompound (I).

[0059] The general preparation of the compounds according to theinvention in accordance with Diagram 1 is described in detailhereinafter.

[0060] Sulfonation of the Naphthalene Derivative (II)

[0061] About 10 mmol of the naphthalene derivative (II) are taken up in2 mL to 100 mL, preferably 3 mL to 80 mL, most preferably about 4 mL, ofacetic anhydride and 10 mmol to 100 mmol, preferably 11 mmol to 80 mmol,particularly preferably 11 mmol or concentrated sulfuric acid is addedat 0° C. to 50° C., preferably 5° C. to 20° C., particularly preferablyabout 18° C. After 2 hours to 16 hours, preferably about 5 hours,stirring at 20° C. to 100° C., preferably about 25° C., the mixture ispoured onto a saturated NaCl solution. The crystals formed are isolated.

[0062] Methylene chloride, diisopropylether, ethyl acetate,trichloromethane, toluene, benzene, or 1,4-dioxane may be used insteadof acetic acid anhydride, while fuming sulfuric acid, sulfur trioxide,chlorine sulfates or combinations thereof may be used as an alternativeto concentrated sulfuric acid.

[0063] Synthesis of the Naphthalene-1-sulfonic Acid Chlorides (III)

[0064] About 10 mmol of the naphthalene-1-sulfonic acids are combinedsuccessively with 10 mmol to 500 mmol, preferably about 90 mmol, ofphosphorus oxytrichloride and 8 mmol to 50 mmol, preferably about 10mmol, of phosphorus pentachloride and heated for 2 hours to 16 hours,preferably about 5 hours, at 20° C. to 100° C., preferably by refluxing.Then the reaction mixture is evaporated down and combined with water.After extraction with organic diluent, the combined organic extracts aredried and freed from solvent. The crude product obtained is used in thesubsequent steps without being purified.

[0065] Instead of the phosphorus oxytrichloride/phosphorus pentachloridemixture, thionyl chloride, phosphorus pentachloride, a phosphoricacid/chlorine mixture, or phosgene may be used. The reaction mayalternatively be carried out in the diluents ethyl acetate, water,acetonitrile, N,N-dimethylacetamide, sulfolane, DMF, hexane, ordichloroethane.

[0066] Synthesis of the Naphthalene-1-sulfonylaminoacetic Acids

[0067] About 10 mmol of the chlorosulfonylnaphthalenes, 10 mmol to 100mmol, preferably 11 mmol to 30 mmol, most preferably about 12 mmol, ofaminoacetic acid and 10 mmol to 100 mmol, preferably 11 mmol to 30 mmol,most preferably about 12 mmol, of sodium hydroxide are dissolved inwater and toluene. The reaction mixture is stirred for 2 hours to 16hours at 0° C. to 110° C., preferably at about 65° C., then the phasesare separated. The aqueous phase is acidified and extracted. Thecombined organic extracts are dried and evaporated down. Purificationmay be carried out by chromatography.

[0068] Triethylamine, potassium carbonate, sodium hydrogen carbonate, orsodium hydride may be used instead of sodium hydroxide, whiletetrahydrofuran, diethylether, dichloromethane, trichloromethane,dioxane, acetone, benzene, ethanol, methanol, ethyl acetate, oracetonitrile may be used instead of toluene.

[0069] Cyclization of the Naphthalene-1-sulfonylaminoacetic Acids (IV)

[0070] About 10 mmol of the naphthalene-1-sulfonylaminoacetic acids arecombined with 10 g to 200 g, preferably about 40 g, of polyphosphoricacid and stirred for 2 hours to 16 hours, preferably about 5 hours, at20° C. to 110° C., preferably 75° C. to 95° C., most preferably at about80° C. Then the reaction mixture is poured onto water and extracted. Thecombined organic extracts are dried and evaporated down. The residue ispurified.

[0071] Method 2

[0072] The compounds of formula (III) obtained as intermediate compoundsin Method 1 are reacted with primary amines to obtain the compounds offormula (V) and then cyclized by the addition of a compound of formulaR²R³C═O in the presence of strong acid to obtain the target compounds(I).

[0073] In order to prepare the compounds of formula (I) wherein R¹ andR² represent hydrogen, paraformaldehyde, trioxane, or formalin may beused and methanesulfonic acid, trifluoroacetic acid, sulfuric acid,phosphoric acid, or polyphosphoric acid may be used as strong acids.

[0074] The general preparation of the compounds according to theinvention in accordance with Diagram 2 is described in detailhereinafter.

[0075] Synthesis of the Naphthalenesulfonamides (V)

[0076] About 10 mmol of the chlorosulfonylnaphthalenes (III) arecombined with an alcoholic solution of the primary amine (10 mmol to1000 mmol in 5 mL to 200 mL, for example, 200 mmol in 50 mL ethanol) andthen heated to 0° C. to 100° C. for 2 hours to 16 hours, preferablyabout 5 hours, preferably by refluxing. Then the reaction mixture isevaporated down and purified.

[0077] Instead of the alcoholic solvent, it is also possible to usetoluene, benzene, trichloromethane, dichloromethane, diethylether,tetrahydrofuran, water, acetonitrile, acetic anhydride, acetone,pyridine, dimethylsulfoxide, dimethylformamide, dioxane, or hexane.

[0078] Cyclization of the Naphthalene-1-sulfonamides (V) to Form theTarget Compounds (I)

[0079] About 10 mmol of the naphthalene-1-sulfonamides are added to 0 mLto 100 mL, preferably 20 mL to 80 mL, most preferably about 40 mL ofmethanesulfonic acid and combined with a solution of 3 mmol to 50 mmol,preferably 4 mmol to 30 mmol, most preferably 5 mmol of trioxane in 0 mLto 100 mL, preferably about 12 mL, of trifluoroacetic acid. The reactionmixture is stirred for 2 hours to 16 hours, preferably 5 hours, at 20°C. to 100° C., preferably 30° C. to 80° C., most preferably about 35° C.and then poured onto ice water. After extraction and drying of thecombined organic extracts, the solution is evaporated down. The crudeproduct is purified.

[0080] Instead of trioxane, it is possible to use paraformaldehyde orformalin, while instead of trifluoroacetic acid it is possible to useboron trifluoride-diethylether, acetic acid, polyphosphoric acid,phosphoric acid, or sulfuric acid. Acetic anhydride or dichloromethanemay be used as possible diluents.

[0081] The new compounds of general formula (I) may be synthesizedanalogously to the following Examples of synthesis. These Examples are,however, intended solely as examples of procedure to illustrate theinvention further without restricting it to the subject matter thereof.

Synthesis of2-methyl-2,3-dihydronaphtho[1,8-de][1,3]thiazine-1,1-dioxide EXAMPLE 1

[0082] 2.21 g of N-methyl-1-naphthalenesulfonic acid amide is dissolvedin 25 mL of methanesulfonic acid at 35° C. and combined with a solutionof 0.30 g of trioxane in 8 mL of trifluoroacetic acid. After 2 hoursstirring at ambient temperature, the reaction mixture is poured onto 300mL of ice water. The solid formed is separated off by filtration, washedwith 100 mL of water, and dried overnight. After crystallization frommethylcyclohexane, the product is isolated as a white solid. Yield: 2.20g; m.p.: 136° C.

Synthesis of 6-chloro-2-methyl-2,3-dihydronaphtho[1,8-de][1,3]thiazine-1,1-dioxide EXAMPLE 2

[0083] 0.45 g of 5-chloro-naphthalene-1-sulfonic acid-N-methylamide isdissolved in 6.8 mL of methanesulfonic acid at 35° C. and combined witha solution of 0.07 g of trioxane in 2 mL of trifluoroacetic acid. After2 hours stirring at 35° C., the reaction mixture is poured onto 100 mLof ice water and the aqueous phase is extracted with ethyl acetate. Theorganic extracts collected are dried with sodium sulfate, evaporateddown in vacuo, and then purified by chromatography. Yield: 0.41 g; m.p.:150° C.

Synthesis of 2,3-dihydronaphtho[1,8-de][1,3]thiazine-1,1-dioxide EXAMPLE3

[0084] Naphthalene-1-sulfonic acid tert-butylamide

[0085] 8 mL of tert-butylamine is placed in 50 mL of chloroform, cooledto 0° C., and 5.75 g of 1-naphthalenic acid chloride in 45 mL ofchloroform are added dropwise. Then the mixture is stirred for 24 hoursat ambient temperature. After concentration by evaporation in vacuo, theresidue obtained is dissolved in dichloromethane and washed with 2 Nhydrochloric acid. The organic extracts collected are dried with sodiumsulfate and evaporated down in vacuo. Yield: 5.48 g.

[0086]2-tert-butyl-1,1-dioxo-1,2-dihydro-1λ⁶-naphtho[1,8-de][1,3]thiazin-3-one

[0087] 4.36 g of naphthalene-1-sulfonic acid tert-butylamide is placedin 80 mL tetrahydrofuran, cooled to -10° C., and 29 mL of N-butyllithium (1.6 molar solution in hexane) are cautiously added dropwise.The mixture is first stirred for 0.5 hour at −10° C., then for 3 hoursat ambient temperature. Then it is cooled to −5° C. and within 0.25hour, CO₂ obtained from dry ice is piped in. The reaction mixture isstirred for 2.5 hours at ambient temperature, then combined with water.The solution is poured onto 4 N hydrochloric acid and extracted withethyl acetate. The organic extracts collected are dried with sodiumsulfate and, after evaporation in vacuo, purified by chromatography.Yield: 0.42 g.

[0088] 2-tert-butyl-2,3-dihydronaphtho[1,8-de][1,3]thiazine-1,1-dioxide

[0089] 0.17 g of2-tert-butyl-1,1-dioxo-1,2-dihydro-1λ⁶-naphtho[1,8-de][1,3]thiazin-3-oneis suspended in 2 mL tetrahydrofuran at ambient temperature and 1.17 mLof borane-tetrahydrofuran complex (1 molar solution) is added. Then themixture is refluxed with stirring for 100 hours, with a total of afurther 8.2 mL of 1M borane-tetrahydrofuran complex solution being addedin several batches. The reaction mixture is combined with 2 mL of 2 Nhydrochloric acid and with 2 mL of methanol, then refluxed for 12 hourswith stirring. 2 mL of ammonia is added and any crystals formed arefiltered off. The filtrate is extracted with ethyl acetate and theorganic extracts collected are dried with sodium sulfate. Afterevaporation in vacuo, the residue obtained is purified bychromatography. Yield: 0.06 g.

[0090] 2,3-Dihydronaphtho[1,8-de][1,3]thiazine-1,1-dioxide

[0091] 0.06 g of2-tert-butyl-2,3-dihydro-naphtho[1,8-de][1,3]thiazin-1,1-dioxide isdissolved in 1 mL of dichloromethane and 0.02 mL of trifluoroacetic acidis added. Then the mixture is stirred for a total of 22 hours at refluxtemperature and for 96 hours at ambient temperature, while during thisperiod a total of 0.07 mL of trifluoroacetic acid is added. The reactionmixture is evaporated down in vacuo and purified by chromatography.Yield: 0.034 g; m.p.: 206° C.-207° C.

Synthesis of[2-(1,1-dioxo-1H-3H-1λ⁶-naphtho[1,8-de]thiazine-2-yl)ethyl]dimethylamineEXAMPLE 4

[0092] 0.028 g of sodium hydride is suspended in 0.5 mL ofdimethylformamide and 0.073 g of2,3-dihydro-naphtho[1,8-de][1,3]thiazine-1,1-dioxide in 1 mL ofdimethylformamide is added. Then 0.053 g of diethylaminoethylchloride-hydrochloride are added batchwise. The reaction mixture isstirred for 18 hours at ambient temperature and then poured onto icewater. The mixture is extracted with dichloromethane and the organicextracts collected are dried with sodium sulfate. After evaporation invacuo, the residue obtained is purified by chromatography. Yield: 0.035g; m.p.: 97° C.-98° C.

Synthesis ofN-(2-methyl-1,1-dioxo-2,3-dihydro-1H-1-naphtho[1,8-de][1,3]thiazin-6-yl)-acetamideEXAMPLE 5

[0093] 5-acetylaminonaphthalene-1-sulfonylchloride

[0094] 1.40 g of 5-acetylaminonaphthalene-1-sulfonic acid and 2.23 g ofphosphorus pentachloride are combined and stirred for 4 hours at 60° C.Then the solution is poured onto ice water and extracted withdichloromethane. The organic extracts collected are dried with sodiumsulfate and evaporated down in vacuo. Yield: 1.10 g.

[0095] N-(5-methylsulfamoylnaphthalene-1-yl)-acetamide

[0096] 1.10 g of 5-acetylaminonaphthalene-1-sulfonyl chloride isdissolved in 8 mL of ethanol and 8 mL of methylamine solution in ethanolare added dropwise. Then the resulting mixture is stirred at refluxtemperature for 3.5 hours and the solvent is distilled off in vacuo. Theresidue is purified by chromatography. Yield: 0.50 g.

[0097]N-(2-methyl-1,1-dioxo-2,3-dihydro-1H-1λ⁶-naphtho[1,8-de][1,3]thiazin-6-yl)-acetamide

[0098] 0.25 g of N-(5-methylsulfamoylnaphthalene-1-yl)-acetamide isdissolved in 3.4 mL of methanesulfonic acid at 35° C. and combined witha solution of 0.027 g of trioxane in 1 mL of trifluoroacetic acid. After6 hours stirring at 35° C., the reaction mixture is poured onto icewater and the aqueous phase extracted with ethyl acetate. The organicextracts collected are dried with sodium sulfate, evaporated down invacuo, and purified by chromatography. Yield: 0.136 g; m.p.: 189°C.-190° C.

Synthesis of2-(1,1-Dioxo-1H,3H-1λ⁶-naphtho[1,8-de][1,3]thiazin-2-yl)-acetamideEXAMPLE 6

[0099] 8-tert-butylsulfamoylnaphthalene-1-carboxylic acid

[0100] 4.36 g of naphthalene-1-sulfonic acid tert-butylamide are placedin 80 mL tetrahydrofuran, cooled to −10° C., and 29 mL of N-butyllithium (1.6 molar solution in hexane) are cautiously added dropwise.The mixture is stirred first for 0.5 hour at −10° C., then for 3 hoursat ambient temperature. It is then cooled to −5° C. and CO₂ obtainedfrom dry ice is piped in within 0.25 hour. The reaction mixture isstirred for 2.5 hours at ambient temperature and then combined withwater. The solution is poured onto 4 N hydrochloric acid and extractedwith ethyl acetate. The organic extracts collected are dried with sodiumsulfate and, after evaporation in vacuo, purified by chromatography.Yield: 1.19 g.

[0101] 1,1-Dioxo-1,1-dihydro-1λ⁶-naphtho[1,8-de][1,3]thiazin-3-one

[0102] 0.25 g of polyphosphoric acid and 0.15 g of8-tert-butylsulfamoylnaphthalene-1-carboxylic acid are combined. Themixture is stirred for 4 hours at 150° C. Then the reaction mixture ispoured onto ice water and the aqueous phase is extracted with ethylacetate. The organic extracts collected are dried with sodium sulfateand evaporated down in vacuo. Yield: 0.07 g.

[0103] 2,3-Dihydronaphtho[1,8-de][1,3]thiazine-1,1-dioxide

[0104] 0.07 g of1,1-dioxo-1,1-dihydro-1λ⁶-naphtho[1,8-de][1,3]thiazin-3-one is dissolvedin 2 mL of tetrahydrofuran and then 1.2 mL of 1 molarborane-tetrahydrofuran complex solution is carefully added dropwise. Themixture is stirred for 18 hours at reflux temperature. The reactionmixture is combined with 1.5 mL of 2 N hydrochloric acid and 2 mL ofmethanol, then stirred for 2 hours at reflux temperature. 2 mL ofammonia is added and any crystals formed are filtered off. The filtrateis extracted with ethyl acetate, the organic extracts collected aredried with sodium sulfate and evaporated down in vacuo. Yield: 0.06 g.

[0105]2-(1,1-Dioxo-1H,3H-1λ⁶-naphtho[1,8-de][1,3]thiazin-2-yl)-acetamide

[0106] 0.011 g of sodium hydride is suspended in 0.5 mL ofdimethylformamide, and 0.06 g of2,3-dihydronaphtho[1,8-de][1,3]thiazine-1,1-dioxide in 1 mL ofdimethylformamide is added. The mixture is stirred for 1 hour at ambienttemperature and then 0.042 g of 2-bromoacetamide are added batchwise.Then the mixture is stirred for 18 hours at ambient temperature. Thereaction mixture is poured onto ice water and extracted withdichloromethane. The organic extracts collected are dried with sodiumsulfate and, after evaporation in vacuo, purified by chromatography.Yield: 0.043 g; m.p.: 195° C.-196° C.

Synthesis of7-hydroxy-2-methyl-2,3-dihydronaphtho[1,8-de][1,3]thiazine-1,1-dioxideEXAMPLE 7

[0107] 0.6 g of7-methoxy-2-methyl-2,3-dihydronaphtho[1,8-de][1,3]thiazine-1,1-dioxideis dissolved in 23 mL dichloromethane and the solution is cooled to −78°C. 2.3 mL of boron tribromide (1 molar solution in dichloromethane) isadded dropwise. Then the mixture is stirred for 24 hours at ambienttemperature. After evaporation in vacuo, the residue is purified bychromatography. Yield: 0.36 g; m.p.: 245° C.-246° C.

Synthesis of methyl2-methyl-1,1-dioxo-2,3-dihydro-1H-1λ⁶-naphtho[1,8-de][1,3]thiazin-7-ylester carboxylate EXAMPLE 8

[0108] 0.11 g of7-hydroxy-2-methyl-2,3-dihydronaphtho[1,8-de][1,3]thiazine-1,1-dioxideand 0.061 mL triethylamine are placed in 2 mL toluene and cooled to 0°C. 0.037 mL of methyl chloroformate are added dropwise. Then the mixtureis stirred for 5 hours at ambient temperature. The suspension is thenpoured onto ice water and extracted with ethyl acetate. The organicextracts collected are dried with sodium sulfate and, after evaporationin vacuo, purified by chromatography. Yield: 0.065 g; m.p.: 161° C.-162°C.

[0109] The following compounds of formula (IA) are obtained, inter alia,analogously to the procedure described hereinbefore: TABLE 1 (IA)

Example R¹ R² R³ R⁴ R⁵ R⁶ m.p. (° C.) 9 CH₃ H H H H Br 226—227 10 CH₃NO₂ H H H H 264—265 11 CH₃ H H OCH₃ H H 174—175 12 CH₃ H H F H H 129—13013 CH₃ H H Br H H 163—164 14 CH₃ H H CH₃ H H 142—143 15 CH₃ H H I H H192—193 16 CH₃ H I H H H 160—161 17 CH₃ H NO₂ H H H 169—170 18 CH₃ H OHH H H 160—161 19 CH₃ N(CH₃)₂ H H H H 20 CH₃ H H H H N(CH₃)₂ 21 CH₃ i-PrH H i-Pr H 22 CH₃ H OCOMe H H H 23 CH₃ H F H H H

[0110] It has been found that the compounds of general formula (I) arecharacterized by their wide range of applications in the therapeuticfield. Particular mention should be made of those applications in whichthe positive modulation of AMPA receptors plays a part.

[0111] The effect of the compounds according to the invention as AMPAreceptor modulators was measured electrophysiologically on cells whichexpress functional AMPA receptors. Investigations were carried out tosee whether the test substances have a positive allosteric influence onthe agonist-induced current.

[0112] The test was carried out at concentrations of between 0.3 μmoland 300 μmol. TABLE 2 Intensification of the Agonist-Induced CurrentExample Activity 1 + 2 ++

[0113] The new compounds can also be used to treat illnesses orconditions in which neuronal networks which require AMPA receptors inorder to function are damaged or limited in their function.

[0114] The compounds of general formula (I) can thus be used indementias, in neurodegenerative or psychotic illnesses and inneurodegenerative disorders and cerebral ischemias of various origins,preferably in schizophrenia or learning and memory disorders.

[0115] The following are also included: epilepsy, hypoglycemia, hypoxia,anoxia, cerebral trauma, brain edema, amyotrophic lateral sclerosis,Huntington's Disease, Alzheimer's disease, sexual dysfunction, disordersof sensory/motor function, memory formation, hyperkinetic behavioralchanges (particularly in children), hypotension, cardiac infarct,cerebral pressure (increased intracranial pressure), ischemic andhemorrhagic stroke, global cerebral ischaemia on stoppage of the heart,acute and chronic neuropathic pain, diabetic polyneuropathy, tinnitus,perinatal asphyxia, psychosis, Parkinson's disease and depression, andrelated anxiety states.

[0116] The new compounds may also be given in conjunction with otheractive substances, such as those used for the same indications or, forexample, with neuroleptics, nootropics, psychostimulants, etc. They maybe administered topically, orally, transdermally, nasally, parenterally,or by inhalation. Moreover, the compounds of general formula (I) or thesalts thereof may also be combined with active substances of otherkinds.

[0117] The compounds of general formula (I) may be given on their own orin conjunction with other active substances according to the invention,and possibly also in conjunction with other pharmacologically activesubstances. Suitable preparations include, for example, tablets,capsules, suppositories, solutions (particularly solutions for injection(s.c., i.v., and i.m.) and infusion), elixirs, emulsions, or dispersiblepowders. The content of the pharmaceutically active compound(s) shouldbe in the range from 0.1 wt. % to 90 wt. %, preferably 0.5 wt. % to 50wt. % of the composition as a whole, i.e., in amounts which aresufficient to achieve the dosage range specified below.

[0118] Suitable tablets may be obtained, for example, by mixing theactive substance(s) with known excipients, for example, inert diluentssuch as calcium carbonate, calcium phosphate, or lactose, disintegrantssuch as corn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc, and/or agents fordelaying release, such as carboxymethyl cellulose, cellulose acetatephthalate, or polyvinyl acetate. The tablets may also comprise severallayers.

[0119] Coated tablets may be prepared accordingly by coating coresproduced analogously to the tablets with substances normally used fortablet coatings, for example, collidone or shellac, gum arabic, talc,titanium dioxide, or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

[0120] Syrups or elixirs containing the active substances orcombinations thereof according to the invention may additionally containa sweetener such as saccharine, cyclamate, glycerol or sugar and aflavor enhancer, e.g., a flavoring such as vanillin or orange extract.They may also contain suspension adjuvants or thickeners such as sodiumcarboxymethyl cellulose, wetting agents such as, for example,condensation products of fatty alcohols with ethylene oxide, orpreservatives such as p-hydroxybenzoates.

[0121] Solutions for injection and infusion are prepared in the usualway, e.g., with the addition of isotonic agents, preservatives such asp-hydroxybenzoates, or stabilizers such as alkali metal salts ofethylenediamine tetraacetic acid, optionally using emulsifiers and/ordispersants, whilst if water is used as the diluent, for example,organic solvents may optionally be used as solvating agents ordissolving aids, and transferred into injection vials or ampoules orinfusion bottles.

[0122] Capsules containing one or more active substances or combinationsof active substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

[0123] Suitable suppositories may be made for example by mixing withcarriers provided for this purpose, such as neutral fats orpolyethyleneglycol or the derivatives thereof.

[0124] Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.,petroleum fractions), vegetable oils (e.g., groundnut or sesame oil),mono- or polyfunctional alcohols (e.g., ethanol or glycerol), carrierssuch as e.g., natural mineral powders (e.g., kaolins, clays, talc,chalk), synthetic mineral powders (e.g., highly dispersed silicic acidand silicates), sugars (e.g., cane sugar, lactose, and glucose)emulsifiers (e.g., lignin, spent sulfate liquors, methylcellulose,starch, and polyvinylpyrrolidone) and lubricants (e.g., magnesiumstearate, talc, stearic acid, and sodium lauryl sulfate).

[0125] The preparations are administered by the usual methods,preferably by oral or transdermal route, particularly orally. For oraladministration, the tablets may of course contain, apart from theabovementioned carriers, additives such as sodium citrate, calciumcarbonate, and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine, and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulfate, and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions, the active substances may be combined with variousflavor enhancers or colorings in addition to the excipients mentionedabove.

[0126] For parenteral use, solutions of the active substances withsuitable liquid carriers may be used.

[0127] The dosage for intravenous use is from 1 mg to 1000 mg per hour,preferably between 5 mg and 500 mg per hour.

[0128] However, it may sometimes be necessary to depart from the amountsspecified, depending on the body weight, the route of administration,the individual response to the drug, the nature of its formulation, andthe time or interval over which the drug is administered. Thus, in somecases, it may be sufficient to use less than the minimum dose givenabove, whereas in other cases, the upper limit may have to be exceeded.When administering large amounts, it may be advisable to divide them upinto a number of smaller doses spread over the day.

[0129] The following examples of formulations illustrate the presentinvention without restricting its scope:

Examples of Pharmaceutical Formulations

[0130] A. Tablets per Tablet active substance 100 mg lactose 140 mgmaize starch 240 mg polyvinylpyrrolidone  15 mg magnesium stearate  5 mg500 mg

[0131] The finely-ground active substance, lactose and some of the maizestarch are mixed together. The mixture is screened, then moistened witha solution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining maize starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size. Tablets per Tablet activesubstance 80 mg lactose 55 mg maize starch 190 mg  microcrystallinecellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch23 mg magnesium stearate  2 mg 400 mg 

[0132] The finely ground active substance, some of the corn starch,lactose, microcrystalline cellulose, and polyvinylpyrrolidone are mixedtogether, the mixture is screened and worked with the remaining cornstarch and water to form a granulate which is dried and screened. Thesodium carboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize. C. Ampoule Soultion active substance 50 mg sodium chloride 50 mgaqua for inj.  5 mL

[0133] The active substance is dissolved in water at its own pH oroptionally at pH 5.5 to 6.5 and sodium chloride is added to make itisotonic. The solution obtained is filtered free from pyrogens and thefiltrate is transferred under aseptic conditions into ampoules which arethen sterilized and sealed by fusion. The ampoules contain 5 mg, 25 mg,and 50 mg of active substance.

We claim:
 1. A compound of formula (I)

wherein: R¹ is a group selected from hydrogen, a C₁-C₆-alkyl groupoptionally substituted by one or more halogen atoms, —SO₂H,—SO₂—C₁-C₆-alkyl, —SO—C₁-C₆-alkyl, —CO—C₁-C₆-alkyl, —O,phenyl-C₁-C₄-alkyl, —C₁-C₄-alkyl-NR⁶R⁷, and —C₁-C₄-alkyl-O—C₁-C₄-alkyl,and C₃-C₆-cycloalkyl, R² and R³, which are identical or different, areeach a group selected from hydrogen, a C₁-C₆-alkyl group optionallysubstituted by one or more halogen atoms, halogen, —NO₂, —SO₂H,—SO₂—C₁-C₆-alkyl, —SO—C₁-C₆-alkyl, —CO—C₁-C₆-alkyl, —OH, —O—C₁-C₆-alkyl,—S—C₁-C₆-alkyl, —C₁-C₄-alkyl-NR⁶R⁷, and —C₁-C₄-alkyl-O—C₁-C₄-alkyl, andC₃-C₆-cycloalkyl, or R¹ and R² together are a C₄-C₆-alkylene bridge; R⁶and R⁷, which are identical or different, are each hydrogen,C₁-C₄-alkyl, or —CO—C₁-C₄-alkyl; R⁴, each of which are identical ordifferent, are each a group selected from a C₁-C₆-alkyl group optionallysubstituted by one or more halogen atoms, phenyl-C₁-C₄-alkyl, halogen,—CN, —NO₂, —SO₂H, —SO₃H, —SO₂—C₁-C₆-alkyl, —SO—C₁-C₆-alkyl, —SO₂—NR⁶R⁷,—COOH, —CO—C₁-C₆-alkyl, —O—CO—C₁-C₄-alkyl, —CO—O—C₁-C₄-alkyl,—O—CO—O—C₁-C₄-alkyl, —CO—NR⁶R⁷, —OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl,—NR⁶R⁷ and an aryl group optionally mono or polysubstituted by halogenatoms, —NO₂, —SO₂H, or C₁-C₄-alkyl; R⁵, each of which are identical ordifferent, are each a group selected from a C₁-C₆-alkyl group optionallysubstituted by one or more halogen atoms, phenyl-C₁-C₄-alkyl, halogen,—CN, —NO₂, —SO₂H, —SO₃H, —SO₂—C₁-C₆-alkyl, —SO—C₁-C₆-alkyl, —SO₂—NR⁶R⁷,—COOH, —CO—C₁-C₆-alkyl, —O—CO—C₁-C₄-alkyl, —CO—O—C₁-C₄-alkyl,—O—CO—O—C₁-C₄-alkyl, —CO—NR⁶R⁷, —OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl,—NR⁶R⁷, and an aryl group optionally mono or polysubstituted by halogenatoms, —NO₂, —SO₂H, or C₁-C₄-alkyl; and n and m, which are identical ordifferent, are each 0, 1, 2, or 3, with the proviso thatnaphtho[1,8-de]-2,3-dihydro-1,1-dioxide-1,2-thiazine is excluded, or anenantiomer or diastereomer thereof, or a pharmacologically acceptablesalt thereof.
 2. The compound of formula (I) according to claim 1,wherein: R¹ is a group selected from hydrogen, a C₁-C₆-alkyl groupoptionally substituted by one or more halogen atoms, —SO₂H,—SO₂—C₁-C₆-alkyl, —SO—C₁-C₆-alkyl, —CO—C₁-C₆-alkyl,—O—C₁-C₄-alkyl-NR⁷R⁸, and —C₁-C₄-alkyl-O—C₁-C₄-alkyl, benzyl, R² and R³,which are identical or different, are each a group selected fromhydrogen, a C₁-C₆-alkyl group optionally substituted by one or morehalogen atoms, halogen, —NO₂, —SO₂H, —SO₂—C₁-C₆-alkyl, —SO—C₁-C₆-alkyl,—CO—C₁-C₆-alkyl, —OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl,—C₁-C₄-alkyl-NR⁶R⁷, and —C₁-C₄-alkyl-O—C₁-C₄-alkyl, or R¹ and R²together are a C₄-C₆-alkylene bridge; R⁶ and R⁷, which are identical ordifferent, are each hydrogen, C₁-C₄-alkyl, or —CO—C₁-C₂-alkyl, and R⁴,which are identical or different, are each a group selected from aC₁-C₆-alkyl group optionally substituted by one or more halogen atoms,halogen, —CN, —NO₂, —SO₂H, —SO₃H, —COOH, —CO—C₁-C₆-alkyl,—O—CO—C₁-C₄-alkyl, —CO—O—C₁-C₄-alkyl, —O—CO—O—C₁-C₄-alkyl, —CO—NR⁶R⁷,—OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl, and —NR⁶R⁷; R⁵, which are identicalor different, are each a group selected from a C₁-C₆-alkyl groupoptionally substituted by one or more halogen atoms, halogen, —CN, —NO₂,—SO₂H, —SO₃H, —COOH, —CO—C₁-C₆-alkyl, —O—CO—C₁-C₄-alkyl,—CO—O—C₁-C₄-alkyl, —O—CO—O—C₁-C₄-alkyl, —CO—NR⁶R⁷, —OH, —O—C₁-C₆-alkyl,—S—C₁-C₆-alkyl, and —NR⁶R⁷; and n and m, which are identical ordifferent, are each 0, 1, or 2, or an enantiomer or diastereomerthereof, or a pharmacologically acceptable salt thereof.
 3. The compoundof formula (I) according to claim 1, wherein: R¹ is hydrogen,C₁-C₄-alkyl, or benzyl, R² and R³, which are identical or different, areeach hydrogen or C₁-C₄-alkyl, or R¹ and R² together are a butylenebridge; R⁴, which are identical or different, are each a group selectedfrom a C₁-C₆-alkyl group optionally substituted by one or more halogenatoms, halogen, —CN, —NO₂, —COOH, —CO—C₁-C₆-alkyl, —O—CO—C₁-C₄-alkyl,-CO—O—C₁-C₄-alkyl, —O—CO—O—C₁-C₄-alkyl, —CO—NR⁶R⁷, —OH, —O—C₁-C₆-alkyl,—S—C₁-C₆-alkyl, and —NR⁶R⁷; R⁵, which are identical or different, areeach a group selected from a C₁-C₆-alkyl group optionally substituted byone or more halogen atoms, halogen, —CN, —NO₂, —COOH, —CO—C₁-C₆-alkyl,—O—CO—C₁-C₄-alkyl, —CO—O—C₁-C₄-alkyl, —O—CO—O—C₁-C₄-alkyl, —CO—NR⁶R⁷,—OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl, and —NR⁶R⁷; and n and m, which areidentical or different, are each 0, 1, or 2, or an enantiomer ordiastereomer thereof, or a pharmacologically acceptable salt thereof. 4.The compound of formula (I) according to claim 1, wherein: R¹, R², R³,which are identical or different, are each hydrogen or C₁-C₄-alkyl; R⁴,which are identical or different, are each a group selected from aC₁-C₆-alkyl group optionally substituted by one or more halogen atoms,halogen, —NO₂, —O—CO—C₁-C₄-alkyl, —O—CO—O—C₁-C₄-alkyl, —O—C₁-C₆-alkyl,and —NR⁶R⁷; R⁵, which are identical or different, are each a groupselected from a C₁-C₆-alkyl group optionally substituted by one or morehalogen atoms, halogen, —NO₂, —O—CO—C₁-C₄-alkyl, —O—CO—O—C₁-C₄-alkyl,—O—C₁-C₆-alkyl, and —NR⁶R⁷; and n and m, which are identical ordifferent, are each 0, 1, or 2, or an enantiomer or diastereomerthereof, or a pharmacologically acceptable salt thereof.
 5. The compoundof formula (I) according to claim 1, wherein: R¹ is methyl, ethyl,isopropyl, n-butyl, or benzyl, or an enantiomer or diastereomer thereof,or a pharmacologically acceptable salt thereof.
 6. The compound offormula (I) according to claim 1, wherein: R¹ is methyl, or apharmacologically acceptable salt thereof.
 7. The compound of formula(I) according to claim 1, wherein: R¹ is methyl; R² and R³ are eachhydrogen; R⁴ and R⁵, which are identical or different, are each halogen;and n and m, which are identical or different, are each 0, 1, or 2, or apharmacologically acceptable salt thereof.
 8. A compound of generalformula (I)

wherein: R¹ is a group selected from hydrogen, a C₁-C₆-alkyl groupoptionally substituted by one or more halogen atoms, —SO₂H,—SO₂—C₁-C₆-alkyl, —SO—C₁-C₆-alkyl, —CO—C₁-C₆-alkyl, —O,phenyl-C₁-C₄-alkyl, —C₁-C₄-alkyl-NR⁶R⁷, and —C₁-C₄-alkyl-O—C₁-C₄-alkyl,and C₃-C₆-cycloalkyl, R² and R³, which are identical or different, areeach a group selected from hydrogen, a C₁-C₆-alkyl group optionallysubstituted by one or more halogen atoms, halogen, —NO₂, —SO₂H,—SO₂—C₁-C₆-alkyl, —SO—C₁-C₆-alkyl, —CO—C₁-C₆-alkyl, —OH, —O—C₁-C₆-alkyl,—S—C₁-C₆-alkyl, —C₁-C₄-alkyl-NR⁶R⁷, —C₁-C₄-alkyl-O—, C₁-C₄-alkyl, andC₃-C₆-cycloalkyl, or R¹ and R² together are a C₄-C₆-alkylene bridge; R⁶and R⁷, which are identical or different, are each hydrogen,C₁-C₄-alkyl, or —CO—C₁-C₄-alkyl; R⁴, which are identical or different,are each a group selected from a C₁-C₆-alkyl group optionallysubstituted by one or more halogen atoms, phenyl-C₁-C₄-alkyl, halogen,—CN, —NO₂, —SO₂H, —SO₃H, —SO₂—C₁-C₆-alkyl, —SO—C₁-C₆-alkyl, —SO₂—NR⁶R⁷,—COOH, —CO—C₁-C₆-alkyl, —O—CO—C₁-C₄-alkyl, —CO—O—C₁-C₄-alkyl,—O—CO—O—C₁-C₄-alkyl, —CO—NR⁶R⁷, —OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl,—NR⁶R⁷, and an aryl group optionally mono or polysubstituted by halogenatoms, —NO₂, —SO₂H, or C₁-C₄-alkyl; R⁵, which are identical ordifferent, are each a group selected from a C₁-C₆-alkyl group optionallysubstituted by one or more halogen atoms, phenyl-C₁-C₄-alkyl, halogen,—CN, —NO₂, —SO₂H, —SO₃H, —SO₂—C₁-C₆-alkyl, —SO—C₁-C₆-alkyl, —SO₂—NR⁶R⁷,—COOH —CO—C₁-C₆-alkyl, —O—CO—C₁-C₄-alkyl, —CO—O—C₁-C₄-alkyl,—O—CO—O—C₁-C₄-alkyl, —CO—NR⁶R⁷, —OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl,—NR⁶R⁷, and an aryl group optionally mono or polysubstituted by halogenatoms, —NO₂, —SO₂H, or C₁-C₄-alkyl; and n and m, which are identical ordifferent, are each 0, 1, 2, or 3, or an enantiomer or diastereomerthereof, or a pharmacologically acceptable salt thereof.
 9. Apharmaceutical composition comprising: (a) a compound of general formula(I) according to claim 1; and (b) a pharmaceutically acceptableexcipient or carrier.
 10. A pharmaceutical composition comprising: (a) acompound of general formula (I) according to claim 8; and (b) apharmaceutically acceptable excipient or carrier.
 11. A method oftreating neurodegenerative diseases and/or cerebral ischaemia of variousorigins in a patient in need thereof, the method comprisingadministering to the patient an effective amount of a compound offormula (I) according to one of claims 1 to
 8. 12. A method of treatingschizophrenia in a patient in need thereof, the method comprisingadministering to the patient an effective amount of a compound offormula (I) according to one of claims 1 to
 8. 13. A method of treatingmemory disorders in a patient in need thereof, the method comprisingadministering to the patient an effective amount of a compound offormula (I) according to one of claims 1 to
 8. 14. A method of treatingdementias in a patient in need thereof, the method comprisingadministering to the patient an effective amount of a compound offormula (I) according to one of claims 1 to 8.